1. Field of the Invention
The present invention relates to an amphiphilic compound having a dendritic branch structure.
2. Description of the Related Art
The amphiphilic compound having a dendritic branch structure according to the present invention is useful for stably fixing, e.g., a water-soluble polymer or oligomer, a polysaccharide or a water-soluble protein on phospholipid vesicles, cell surfaces or hydrophobic surfaces with a minimum modification of these materials. Further, the amphiphilic compound having a dendritic branch structure according to the present invention is also useful as a surface modifier for various substances including, for example, a vesicle or microsphere exhibiting a specific recognizing ability to cells or proteins, a gel for column separation, various sensors and a cell culture substrates, and is also useful as an emulsifier, a stabilizer, a dispersant, a solubilizer, an admixture, a wetting agent, a penetrating agent, or a viscosity modifier for go medicines, foods, cosmetics and dyes.
Surfaces modified with a water-soluble polymer chain such as polyoxyethylene are excellent in biocompatibility, and can be utilized as a raw material for, e.g., an artificial organ (e.g., artificial vessel), an artificial cell, or an artificial blood. Further, by introducing a functional molecule into the surface, the surface can be furnished with a specific function. The introduction of such a water-soluble polymer chain to the surface is usually performed through a covalent bond. It can be said that a methodology for stably fixing such a water-soluble polymer chain to the surface by utilizing intermolecular interaction has not yet been established until now.
As is well known, a vesicle with phospholipid bilayer membrane is accompanied with various problems that it often aggregates or fuses, and that the residence time thereof in blood is relatively short. These problems have been solved by mixing charged lipid or cholesterol into the lipid component constituting the vesicle, and modifying the surface of the vesicle with polyoxyethylene or saccharide. A lipid composed of diacylphosphatidylethanolamine or cholesterol having polyoxyethylene bonded thereto is widely employed as a stabilizer for vesicles. It is reported however that the diacyl lipid having such a water-soluble polymer bonded thereto is eliminated from the phospholipid vesicle (J. R. Silvius and M. J. Zuckermann, Biochemistry, 32, 3153, 1993).
It is now extensively studied that a functional protein (or a portion thereof) that is capable of recognizing a specific molecule or a specific cell surface is carried on a surface of a vesicle, which is utilized as a drug transporter or as artificial cells. Further, since it is generally difficult to procure such a functional protein from cells, and hence only a trace amount is obtainable from cells, it is now adopted a method (recombinant system) wherein only a water-soluble recognizing function site of the protein is permitted to secrete into gene recombinant fungus to produce a large amount of the functional protein. In order to carry this water-soluble protein on the surface of phospholipid vesicle bilayer membrane, it is required to introduce a hydrophobic group into the membrane. For example, a method of coupling a lipid (diacylphosphatidylethanolamine) to the amino group, carboxyl group or thiol group of protein by an appropriate means has been frequently employed. However, since the phospholipid employed in this case is double-legged, it is required, in order to stably introduce the hydrophobic group into the surface of bilayer membrane, that the lipid be coupled at a plurality of sites so as to well-balance the hydrophobic site with the hydrophilic site. If this coupling is performed non-selectively, the functions are often impaired by the steric hindrance of the active site due to the coupled alkyl chain or by the coupling of the hydrophobic group to the active site. Further, the boundary between the hydrophobic site and the hydrophilic site is not clear, and it would be very difficult to introduce the hydrophobic group in a uniformly aligned manner into the surface of vesicle.
A dendritic sphere (dendrimer) has a large number of functional groups at its branched ends, and a plurality of functional molecules can be coupled thereto in conformity with the number of generation (a general review is disclosed by e.g., J. I. R. Moors and F. Vogtle, Angew. Chem. Int. Ed. Engl., 33, 2413, 1994). A dendrimer which is constituted from amino acids can be easily obtained by means of ordinary peptide-synthesizing method, and is excellent in both biodegradability and biocompatibility. A dendrimer constituted by lysine is first reported by R. G. Denkenwalter, et al (U.S. Pat. No. 4,289,872) (issued on Sep. 15, 1981). Since then, a synthesizing method by way of solid-phase peptide synthesis has been established (J. P. Tam et al., Proc. Natl. Acad. Sci., USA, 85, 5409, 1988), wherein a derivative thereof where a bioactive peptide or a saccharide is coupled to the branched terminal amino group is reported. An amphiphilic compound wherein polyoxyethylene is coupled to the core portion of hydrophobic dendron is already reported and is now studied on the utilization thereof as a novel functional material (I. Gitsov et al., Angew. Chem. Int. Ed. Engle., 31, 1200, 1992, T. M. Chapman et. al., J. Am. Chem. Soc., 116, 11195, 1994). Recently, an amphiphilic dendrimer wherein a plurality of hydrophobic groups are coupled to the branched terminals (A. P. H. J. Schenning et al., J. Am. Chem. Soc., 120, 8199, 1998) or a dendrimer having protein coupled thereto (P. Singh, Bioconjugate Chem., 9, 54, 1998) are reported.
An object of the present invention is to provide a novel amphiphilic compound which is capable of stably fixing a water-soluble polymer onto a surface structure by taking advantage of intermolecular interaction, thereby enabling the water-soluble polymer to be carried thereon without giving any damage to the function thereof.